Elastic laminae are extracellular matrix constituents that not only contribute to the stability and elasticity of arteries but also play a role in regulating arterial morphogenesis and pathogenesis. We demonstrate here that an important function of arterial elastic laminae is to prevent monocyte adhesion, which is mediated by the inhibitory receptor signal regulatory protein (SIRP) ␣ and Src homology 2 domain-containing protein-tyrosine phosphatase (SHP)-1. In a matrix-based arterial reconstruction model in vivo, elastic laminae were resistant to leukocyte adhesion and transmigration compared with the collagen-dominant arterial adventitia. The density of leukocytes within the elastic lamina-dominant media was about 58 -70-fold lower than that within the adventitia from 1 to 30 days. An in vitro assay confirmed the inhibitory effect of elastic laminae on monocyte adhesion. The exposure of monocytes to elastic laminae induced activation of SIRP ␣, which in turn activated SHP-1. Elastic lamina degradation peptides extracted from arterial specimens could also activate SIRP ␣ and SHP-1. The knockdown of SIRP ␣ and SHP-1 by specific small interfering RNA diminished the inhibitory effect of elastic laminae, resulting in a significant increase in monocyte adhesion. These observations suggest that SIRP ␣ and SHP-1 potentially mediate the inhibitory effect of elastic laminae on monocyte adhesion.Arterial elastic laminae have long been considered a structure that determines the strength and elasticity of blood vessels (1-6). Recent studies, however, have demonstrated that arterial elastic laminae also participate in the regulation of arterial morphogenesis and pathogenesis (7-12). An important contribution of elastic laminae is to confine smooth muscle cells (SMCs) 2 to the arterial media by inhibiting SMC proliferation (8, 9) and migration (10), thus preventing intimal hyperplasia under physiological conditions. Arterial elastic laminae also exhibit thrombosis-resistant properties. When implanted in an artery, elastic lamina scaffolds are associated with significantly lower leukocyte adhesion and thrombosis compared with collagen matrix scaffolds (10).These observations suggest an inhibitory role for elastic laminae relative to collagen matrix. Although such a role is well documented, the mechanisms remain poorly understood.Leukocytes are known to express the inhibitory receptor SIRP ␣ (also known as Src homology 2 domain-containing tyrosine phosphatase substrate-1), a transmembrane glycoprotein receptor that exerts an inhibitory effect on cell mitogenic (13-18) and inflammatory (19,20) activities. Upon ligand binding, SIRP ␣ transmits inhibitory signals through tyrosine phosphorylation of its intracellular immunoreceptor tyrosine-based inhibitory motif (15-18, 21, 22). The phosphorylation of the immunoreceptor tyrosine-based inhibitory motif initiates the recruitment of Src homology 2 domain-containing protein-tyrosine phosphatase (SHP)-1 to SIRP ␣, which is known as a substrate of SHP-1 (21, 22). The recruitment of SH...